Psychoneuroimmunology: synopsis of its history, classes of evidence and their implications

Definition

Psychoneuroimmunology is the transdisciplinary scientific field concerned with interactions between brain (mind/behavior) and the immune system and their clinical implications (1). The field is usually referred to as psychoneuroimmunology or "PNI". The psychologist Robert Ader coined the term in the late 1970's, but it is also known by the equally ponderous terms neuroimmunomodulation and, less commonly, as neuroendocrinoimmunology or behavioral immunology. Its clinical aspects range from an understanding of the biological mechanisms underlying the influence of psychosocial factors on the onset and course of immunologically resisted and mediated diseases to an understanding of immunologically-generated psychiatric symptoms. Its basic scientific aspects involve understanding the complex interaction of neuroendocrine and immunologically generated networks in maintaining health and combating disease. Psychoneuroimmunology may provide a basis for understanding the biological dynamics of humanistic medicine and of alternative or complimentary medical techniques and offers the hope of developing new non-linear models of health and disease.

By its very nature, psychoneuroimmunology bridges the traditional disciplines of psychiatry, psychology, neurology, endocrinology, immunology, neuroscience, internal medicine, and even surgery (wound healing). Interdisciplinary collaboration is generally essential and intrinsic to its research. The field is rapidly growing, as evidenced by the 14 chapters of the 1981 First Edition of it major textbook, the 46 chapters of its 1991 Second Edition (2) and the 80 chapters of the 1999 three-volume Third Edition.

History

Ancient and pre-modern wisdom reflected awareness of body-mind bi-directional interaction. Aristotle said, "Psyche and body react sympathetically to each other, it seems to me. A change in the state of the psyche produces a change in the structure of the body, and conversely, a change in the structure of the body produces a change in the state of the psyche." Sir Francis Bacon similarly suggested, "Let us enquire how and how far the humours and affects of the body do alter and work upon the mind, or again, how and how far the passions or apprehensions of the mind do alter or work on the body."

Wise physicians have long been aware of the role of emotions in the onset and course of immunologically resisted and mediated diseases. Sir William Osler is reported to have said that it is just has important to know what is going on in a man¡¦s head as his chest in order to predict the outcome of pulmonary tuberculosis. The British physiologist George Day noted increasing difficulty in adjustment in the 18-24 months prior to the onset of the disease and said, that psychological factors can and do influence the course of tuberculosis, once its is established, can be witnessed by anyone who has the opportunity of watching a patient's progress over a reasonably long period (3). Over a course of years since the 1940's many psychosomatic observations were made regarding emotional factors in the onset and course of autoimmune diseases, mainly rheumatoid arthritis, but including systemic lupus erythematosis (SLE), Graves disease/thyroiditis, and others (4). In perhaps the most intriguing observation of this period, it was found that physically healthy relatives of patients with rheumatoid arthritis who had in their sera the autoantibody characteristics of that disease, rheumatoid factor (anti-immunoglobulin G), were better adjusted psychologically, on average, than those lacking the factor, suggesting that psychological well-being might have a protective influence in the face of a genetic vulnerability (5). Conversely, at least one autoimmune disease, SLE, can produce psychiatric symptoms, even as an initial clinical feature (6). The relatively voluminous literature, of highly varied quality, on personality factors predisposing to cancer and psychological factors predictive of outcome are harder to interpret psychoneuroimmunologically, since only some cancers (such as malignant melanoma, non-Hodgkin's lymphoma, and some breast cancers) clearly are resisted immunologically, although the case for immunological resistance to metastatic dissemination (via natural killer cell cytotoxicity) is impressive (7,8).

The scientific foundations of psychoneuroimmunology are the subjects of a compilation of historical papers, a few of which will be cited (9). By the late 1950s and early 1960s, animal experiments implied that stress could affect both humoural and cellular immunity. Rasmussen, Marsh, and Brill found that mice subjected to avoidance learning stress were more susceptible to herpes simplex virus infection. Wistar and Haldemann found that the same stress prolonged the retention of homografts. The first direct experimental evidence of stress effects on immunity was that of a reduction of antibody response to antigen as a result of group housing stress in rodents by Vessey and by Solomon (1960s). About the same time, Solomon, Levine, and Kraft demonstrated that early life experience (infantile handling) might affect antibody response in adult life. The larger area of immunological abnormalities that occur in conjunction with mental illnesses began with work of Solomon and Fessel on abnormal immunoglobulin levels and brain-reactive antibodies in some patients with schizophrenia. The most definitive early research in psychoneuroimmunology, largely overlooked in the West, was that of Korneva and Khai working in then-Leningrad. In 1963, they reported that destructive electrolytic lesions in the dorsal hypothalamus of rabbits led to a suppression of the development of complement-fixing antibodies and prolonged retention of antigen in the blood. Thus, they had proven that the brain was involved in immunoregulation, a subject of speculation in Solomon and Moos 1964 paper, Emotions, Immunity, and Disease (3), sometimes referred to as a marker of the beginning of the field. A number of prescient papers were published in the 1960s and 1970s by the Yugoslav immunologist B.D. Jankovic. For example, he pointed out antigenic similarities between brain and immunological proteins. The most critical paper to establish credibility and significance of brain-immune communication, however, was that of Robert Ader and Nicholas Cohen in 1975 on taste-aversion conditioned immunosuppression. If a conditioned stimulus (saccharin) could produce the immunosuppression of an unconditioned stimulus (the drug cyclophosphamide), then brain and learning must relate to immunological responses. Subsequently, Ader and Cohen discovered, relevantly both clinically and in regard to the nature of the placebo response, the ability to utilize this type of conditioning to prolong the life of mice with an autoimmune disease, lupus, by treatment mainly with saccharin (10). Remarkably, it was only after a general acceptance of the phenomenon of conditioning of immunity (which was subsequently shown to be able to be accomplished in up-regulatory as well as down-regulatory directions) was it realized that in 1926 the phenomenon had been demonstrated regarding peritoneal inflammation by Metalnikov and Chorine working at the Pasteur Institute, science truly before its time. The critical link between the immune system and the brain in the neuroendocrine-immune axis was convincingly demonstrated by Besedovsky and Sorkin in the late 1970s. They showed that immune activation (antigenic stimulation) triggers the hypothalamic-pituitary-adrenal (HPA) axis in an immunoregulatory role. The next milestone was the then-controversial finding by Edwin Blalock that immunologically competent cells (lymphocytes) can synthesize hormones (ACTH) and neuropeptides (Ograve;-endorphin), formerly thought only produced by neuroendocrine cells (11).

Classes of Evidence of Central Nervous System (CNS)-Immune Interactions

There are a variety of categories of evidence--experimental and naturalistic, basic and clinical, animal and human, in vitro and in vivo, medical and psychiatric--for bi-directional communication between the central nervous system and various components of the immune system. Teleologically, it makes sense that these two systems should be linked. Both relate the organism to the outside world and assess its components as harmless or dangerous; both serve functions of defense and adaptation; both possesses memory and learn by experience; both contribute to homeostasis; errors of defense by each can produce illness, e.g., autoimmunity or allergies on the one hand and phobias or panic on the other. Blalock has referred to the immune system as a sixth sense, forwarding information about the environment to the brain about molecular and cellular aspects of the environment not accessible by the five senses (11). The classes of evidence for CNS-immune interaction, some of which have been mentioned, include: direct (lesion) evidence of brain region control of immunity and of innervation of immune organs; psychological (trait and state) factors in the onset and course of immunologically resisted (infectious and neoplastic) and mediated (autoimmune and allergic) diseases; influences of stress-response hormones on immunity; effects of neurotransmitters and neuropeptides on immunity; effects of experimental stress on immunity in animals; effects of experimental and naturalistic life stress and exercise on immunity in humans; behavioral modifiers of stress effects on immunity in animals and humans; effects of psychoactive drugs on immunity; correlation of individual psychological differences with immunity in animals and man; occurrence of immunological abnormalities in conjunction with mental illnesses (depression and schizophrenia); influence of products of the immune system on the CNS, including immunologically-induced behaviors; and alteration by psychological intervention and exercise of immunity and the course of immunologically -related diseases .

Regarding direct evidence of neural modulation of immunity (12), pioneering work on the hypothalamus was mentioned. Hypothalamic neurons fire in spatial and sequential ways after antigen administration, and HPA axis is activated by antigen and pro-inflammatory cytokines in a stress-like way. Immune organs, including thymus, spleen, and bone marrow, receive sympathetic innervation with synapse-like junctions between nerve endings and immunocytes. Immunity is regulated in a cerebrocortical laterally specific way with the left cortex influencing T cell maturation and function.

Emotional factors in the onset and course of autoimmune diseases include claims of personality trait/coping style predisposing factors such as tension and insecurity, shyness, difficulty in expressing feelings and in being assertive, martyr type and masochistic characteristics, and sensitivity to the anger of others. Psychological state factors include loss/bereavement and depression and situational factors such as loss of previously successful modes of adaptation (13). Negative affect and failure of coping have been related to rate of progression, degree of incapacitation, and poorer response to medical treatment, particularly of rheumatoid arthritis. In regard to allergies, a less well-studied area, stress, anxiety, and depression have been related to both delayed (T cell) and immediate (B cell) hypersensitivities and to atopic dermatitis and asthma (14, 15, 16). There is a somewhat controversial literature suggesting that hypnosis can alter immediate and delayed hypersensitivity (17).

The psychoneuroimmunology of cancer is an area of increasing attention (18). The antigenicity of neoplasms vary and, thus, the ability of immune system to resist specific cancers. Immunotherapies are gaining attention, particularly for treatment of melanoma, lymphomas, and breast cancer. ¡¡±Cooley¡¦s toxins¡¨ that had some efficacy before the advent of chemotherapy are now known to have been powerful immune stimulants. The natural killer (NK) cell, a non-B, non-T lymphocyte, has cytotoxic activity that is non-specific and non-histocompatibility locus antigen (HLA) restricted. Many experimental and clinical studies in human and animals have shown this cell type to be sensitive to influence in numbers and activity by stressors and psychosocial factors. The NK cell may play a role in immune surveillance against newly-emerged neoplastic cells but is clearly known to play an important role in prevention of metastatic spread of cancer. Stress increases metastatic spread of mammary carcinoma in the rat via suppression of NK cell cytotoxicity (18). Psycho-oncology, which is the subject of a separate section of this text, is concerned with quality as well as duration of life in cancer patients. Psychoneuroimmunology suggests these two are linked. At this date, only one psychotherapeutic intervention study included immunological as well as clinical outcome variables, that of Fawzy and colleagues (19). When compared with controls, patients with malignant melanoma undergoing a structured psychiatric group intervention at 6 month follow-up showed more effective coping, less distress, and greater stimulability of NK cells. Intervention patients showed less recurrence and greater survival 6 years later.

Psychoneuroimmunology, stress and infection, the topic of old observations and early experimental work, is now the focus of rigorous research (20). Subjects given a variety of cold-causing viruses intranasally developed both antibody evidence of infection and clinical colds in a dose-response manner in proportion to increases in degree of perceived psychological stress (21). There is much confirmation of earlier work on stress effects on viral and bacterial (including mycobacterial) infections in experimental animals.

Stress responsive hormones, including but not limited to adrenal corticosteroids and catecholamines, have a myriad of effects of various aspects of the immune response in both down- and up-regulatory fashion (22). Often hormones affect immunity in an ¡§inverted U shaped¡¨ way, suppressive at either abnormally high or low levels. The HPA axis, as mentioned, triggered itself by immunological as well as psychological events, is immunoregulatory, and both corticotropin-releasing factor (CRF) and adrenocorticostimulating hormone (ACTH) have direct effects on immunity in addition to those via induction of release of cortisol. Growth hormone increases T and NK cell functions in aged animals. Prolactin antagonizes glucocorticoid-induced immune suppression. Gonadal hormones affect immunity. NK cell activity is higher in the luteal phase of the menstrual cycle (which should influence surgeons in the timing of cancer surgery in pre-menopausal women). Cellular immunity is depressed during pregnancy. Thyroid hormones may stimulate NK activity, affect T cell development, and modulate the affect of cytokines on immune cells (23). Neuropeptides, which are stress responsive (24), have multiple immunological effects (25), and have even been referred to as ¡§conductors of the immune orchestra¡¨ (26). Beta-endorphin is a stimulant of NK cell activity. Substance P, co-released with norepinephrine at sympathetic nerve endings, may be particularly important in local immunity (and psychological influences thereon). Vasoactive intestinal peptide (VIP) modulates immunoglobulin production. The sympathetic neurotransmitter (also a hormone) norepinephrine mobilizes NK cells into the circulation and probably is responsible for their increase during acute stress. Cerebral catecholamines and indolamines (e.g., serotonin) are released by immune activation and pro-inflammatory cytokines like interleukin-1 (IL-1), which, in turn, probably influence neuroimmunomodulation (23).

Experimental stress and immunity in animals, already mentioned in pioneering studies, is the subject of a very large literature (27). Type, duration, intensity, timing (in relation to antigen administration), and controllability of the stressor are all relevant to its immunological impact. In primates, social support is a modifier of stress effects (28). Behavioural response to the stressor, such as defeat posture, may be critical to the immunological outcome.

Acute experimental stress in humans (akin to fight/flight reactions), such as mental arithmetic, generally results in a transient increase in ¡§first-line-of-defense¡¨ immunity, such as NK cell numbers and activity, and such effects have psychophysiological correlates (29).

Naturally occurring human life stresses, both acute like examinations and chronic like caregiving for patients with Alzheimer¡¦s disease, adversely affect a wide array of immune measures (30). These include: T cell function, NK cell activity, antibody response to immunization, macrophage function, activation of latent viruses like herpes simplex (controlled by cellular, not humoural immunity). Such effects increasingly are being shown to have health implications. Social support can ameliorate stress effects. Natural disasters can have prolonged effects on immunity (31).

Exercise can affect immunity positively or negatively (32). Acute aerobic exercise transiently increases NK cell numbers and activity. Overtraining without adequate periods of rest and recovery can diminish NK and T cell functions and increase incidence of infectious diseases. Several studies have reported an association between physical inactivity and risk of colon cancer, and animal tumourigensis experiments tend to show that regular exercise reduces tumour burden. Even moderate exercise in very frail elderly people can reduce both NK and T cell functions, quite contrary to the effects of moderate endurance exercise on increasing resistance to infectious disease in normals. Exercise increases lifespan in rats fed ad libitum. The combination of exercise and severe food restriction found in patients with anorexia nervosa leads (as in experimental animals) to morbid immunosuppression.

Drugs of abuse, particularly alcohol, have adverse effects on various aspects of immunity and susceptibility to infectious diseases (33, 34). Fetal alcohol exposure can permanently affect endocrine and immune responses. Alcohol inhibits production of pro-inflammatory cytokines, reduces NK cell activity and suppresses B and T cell immunity. Alcoholics are infection-prone. Although HIV-seronegative heroin addicts generally have reduced immune functions, persons maintained on methadone in a state of steady tolerance have normal immunity. Marijuana suppresses production of interferon ƒÑ and ƒÒ and cytolytic activity of macrophages. Other psychoative drugs often have immune effects. Benzodiazepines antagonize CRF-induced suppression of NK cell activity and may, thus, modify stress effects on immunity (35).

Individual differences in behaviour, coping styles, and psychological traits may be accompanied by differences in immunological characteristics. Inbred female mice that showed spontaneous fighting behaviour showed greater immunological resistance to a virus-induced tumour (36). A pessimistic explanatory style correlated with lower measures of cell-mediated immunity (37).

The topic of immunologic abnormalities that occur in conjunction with major mental illnesses needs to be divided between those associated with depression (affective disorders) and with schizophrenia, a much more muddled area of research. Given that the central nervous system and the immune system have intimate linkages, as are being ever more fully elucidated by psychoneuroimmunology, it would seem to follow that major functional perturbations in one system would be reflected in the other. Some of these may have implications for physical health, implying the inextricability of mental and physical health. However, the contribution of immunological processes to the etiology of mental illness is highly problematic, unlike to that of some neurological disorders, particularly multiple sclerosis, an autoimmune disease.

Important decrements in immunological functions have been well documented in depression, particularly major depressive disorder (38). In major depressive disorder, T cell function declines in an age-dependent way. Thus, young persons (20s, 30s) with a significantly elevated score on a psychological test of depression might have no T cell functional decrement; whereas, an elderly person with the same depression score would be likely to suffer a clinically significant decline. Intensity and duration of depressive symptoms are relevant. In contrast, depression-associated declines in NK cell cytotoxicity are age-independent. Latent virus activation occurs in depression. It is noteworthy that depression is associated not only with immunosuppression but with signs of immune activation (such as lymphocyte cell surface activation markers like HLA-DR). Depression even has been referred to as an ¡§inflammatory disease¡¨. Effective treatment of depression by whatever modality is accompanied by gradual returns of immune functions to normal. (Tricyclic antidepressant drugs are somewhat immunosuppressive in vitro; whereas, lithium may have some immunostimulatory properties.)

It is beyond the scope of this section to sort out all the myriad of immunological abnormalities that have been found in some patients with schizophrenia, particularly longstanding claims that schizophrenia itself might be an autoimmune disease (39). There have been a number of claims, largely based on epidemiological evidence, that schizophrenia is viral or post-viral in etiology (40). A variety of abnormalities of levels of different classes of immunoglobulins in serum and cerebrospinal fluid has been inconsistently reported in conjunction with schizophrenia. It does appear that, relative to normal controls, there is a higher incidence of a variety of autoantibodies, including rheumatoid factor (anti-IgG) and anti-nuclear factor, in schizophrenia. Much more controversial has been the concept of schizophrenia as an autoimmune disease based on a considerable number of reports of antibrain antibodies (usually heterologous) in schizophrenic patients¡¦ sera, studies begun by Fessel and particularly promoted by Heath, whose claims of replicating schizophrenic-like symptoms by injection of patients¡¦ immunoglobulins into monkeys and humans were never replicated. An autoimmune theory of schizophrenia remains attractive because of evidence that other autoimmune diseases have both genetic and psychological predisposing and exacerbating factors. More modern work has suggested immunopathology of neurotransmitter receptors, both serotonergic and dopaminergic. (Autoantibodies can act as blockers or stimulants of neurotransmitter receptors, as in the cases of myasthenia gravis and Graves¡¦ disease respectively. It has been postulated that an autoantibody could act as a dopamine agonist in schizophrenia.) Abnormalities in cytokine production, particularly of IL-2, have been found. An early observation of Hirata-Hibi of morphological abnormalities in lymphocytes of many patients with schizophrenia (particularly those with ¡§negative¡¨ symptoms) and some of their family members seems to have held up in replication studies. The cell likely is an activated T cell. These many, varied, and generally inconsistent findings, possibly reflective of subtypes of schizophrenia, are hard to interpret. The linked neuropsychological-immunological perturbation hypothesis seems the most conservative.

The immune system affects brain and behaviour, especially via the effects of immune cytokines on the CNS (41). Although cytokines are relatively large molecules, some, particularly interleukin-1, can cross the blood-brain barriers via active transport. IL-1 also is produced in the brain, not only by microglia, which are CNS-resident macrophages, but also by astrocytes. Peripheral IL-1 can affect the brain, including its cytokine production, via stimulation of afferent fibers of the vagus nerve. There are cytokine receptors in the brain, including for IL-1, IL-8, and interferon, both on glial cells and neurons. Cytokines play a role in the development and regeneration of myelin-producing oligodendrocytes. Brain cytokines play a role in immune effector mechanisms as regulated by the brain, including a role in brain infection and inflammation. Cytokines are relevant to progression of multiple sclerosis, gliomas, HIV-associated dementia, brain injury, and, probably, Alzheimer¡¦s disease. Pro-inflammatory cytokines, particularly IL-1 and tumour necrosis factor (TNF), are responsible for sickness behavour that includes fever, sleepiness, anorexia, and fatigue. Sickness behaviour is adaptive. Microbes grow less well at high body temperature, which is also immunostimulatory. Production of IL-1 is facilitated by slow-wave sleep. Low blood sugar ¡§starves¡¨ bacteria. Fatigue conserves energy for battling infection. Not ¡§listening to the body¡¨ and ignoring sensory messages that are immunologically induced and not modifying behaviour appropriately for illness can adversely affect course of infection. There is some evidence that chronic fatigue syndrome, (CFS), which may occur following a viral infection, physical exhaustion, or psychological stress and which may be accompanied by depression, is related to inappropriate cytokine signaling as if there were infection, and elevated levels of IL-1 have been reported (42). Unlike depression, which is usually associated with elevated levels of cortisol, CFS is associated with low levels. Evidence of immunosuppression and activation occur in both CFS and depression. IL-1 can produce both cognitive defects and lowered pain threshold in animals. Cognitive defects, myalgias, and headaches are often prominent symptoms of CFS. Therapeutic use of cytokines, particularly interferon, can produce psychiatric symptoms; psychotic, affective, or anxious.

Links between brain and behavior and between psychiatry and medicine are well illustrated by the substantial research on the influence of psychosocial factors on the course of human immunodeficiency virus (HIV) infection and AIDS (43). Sustained depressed mood and negative expectancies, especially when complicated by bereavement, are associated with more rapid decline of CD4+ helper T cells and an increase in other markers of progression (such as the activation marker ƒÒ-2 microglobulin), as is lack of open acknowledgment of sexual orientation (being ¡§in the closet¡¨). Passive coping (including denial and disengagement) is inversely related to long-term CD4 cell count. Long-survivors with clinical AIDS and those who remain asymptomatic for prolonged periods of time in the face of very low CD4 counts seem to be those who have good coping skills, lead meaningful lives, find new meanings as a result of illness, are relatively not distressed, and are emotionally expressive and assertive. As stated, HIV-associated dementia, which is reversible in its early stages, appears to be closely related to the action of pro-inflammatory cytokines, particularly TNF, on neurons. Psychiatric symptoms, besides cognitive defects, probably also cytokine-induced, also occur in conjunction with HIV infection (primarily of microglia) of the brain including apathy, withdrawal, psychosis, and regressive behaviours.



<B>Towards New Models of Health and Illness</B>



Health can be viewed as the capacity of the organism to regulate its own behaviour and physiology and produce coordinated response patterns to challenges. The two systems mediating interaction with the environment, the central nervous and immune systems, communicate with each other and, as stated, can be thought of as a single integrated system for adaptation and defense. Psychoneuroimmunology is dissolving dualisms of mind-body, body-environment, and individual-population. In realizing that the states of the medical body are correlated with individual¡¦s bodily experienced meanings, philosopher David Levin and this author expressed hope that patients will experience their bodies and themselves in new ways (44). Somatic awareness is akin to psychological insight, and each has a role in maintenance of physical and mental health. Patients may realize that the body he or she presents for treatment is a body of integrated mental/somatic awareness, of meaningful experience, and is influenced by his or her own sensitivity. Psychoneuroimmunology (PNI) should not only help to understand the pathophysiology and psychophysiology of disease in a more systems theory-oriented way but also to value the doctor-patient relationship and the patient¡¦s own role in recovery from disease and maintenance of health. Thus, psychoneuroimmunology provides a scientific basis for the practice of humanistic medicine.

Referencias

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5. Solomon, G.F and Moos, R.H. (1965) The relationship of personality to the presence of rheumatoid factor in asymptomatic relatives of patients with rheumatoid arthritis. Psychosomatic Medicine 27; 350-360.

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43. Nott, K. and Vedhara K., ed. Psychosocial and Biomedical Interactions in HIV Infections. Chur (Switzerland): Harwood Academic Publishers, in press (1999).

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